Corticotropin releasing factor antagonists

A compound of the following formula II

• or a pharmaceutically acceptable salt thereof, wherein
• A is —CR7 or N;
• B is —NR1R2, —CR1R2R11, —C(═CR2R12)R1, —NHCHR1R2, —OCHR1R2, —SCHR1R2, —CHR2OR1, —CHR1OR2, —CHR2SR1, —C(S)R2, —C(O)R2, —CHR2NR1R2, —CHR1NHR2, —CHR1N(CH3)R2, or —NR12NR1R2;
• Y is CH or N;
• R1 is C(O)H, C(O)(C1–C6 hydrocarbyl), C(O) (C1–C6 hydrocarbylene)(C3–C8 cyclohydrocarbyl), C(O)(C3–C8 cyclohydrocarbylene) (C3–C8 cyclohydrocarbyl), C(O)(C1–C6 hydrocarbylene)(C4–C8 heterocyclohydrocarbyl), —C(O)(C3–C8 cyclohydrocarbylene) (C4–C8 heterocyclohydrocarbyl), C1–C6 hydrocarbyl, C3–C8 cyclohydrocarbyl, C4–C8 heterocyclohydrocarbyl, —(C1–C6 hydrocarbylene (C3–C8 cyclohydrocarbyl), C3–C8 cyclohydrocarbylene)(C3–C8 cyclohydrocarbyl), —(C1–C6 hydrocarbylene)(C4–C8 heterocyclohydrocarbyl), —(C3–C8 cyclohydrocarbylene)(C4–C8 heterocyclohydrocarbyl), or —O-aryl, or —O—(C1–C6 hydrocarbylene)-aryl;
• wherein said aryl, C4–C8 heterocyclohydrocarbyl, C1–C6 hydrocarbyl, C3–C8 cyclohydrocarbyl, C3–C8 cyclohydrocarbylene, and C1–C6 hydrocarbylene groups may each independently be optionally substituted with from one to six fluoro and may each independently be optionally substituted with one or two substituents R8 independently selected from the group consisting of C1–C4 hydrocarbyl, —C3–C8 cyclohydrocarbyl, hydroxy, chloro, bromo, iodo, CF3, —O—(C1–C6 hydrocarbyl), —O—(C3–C5 cyclohydrocarbyl), —O—CO—(C1–C4 hydrocarbyl), —O—CO—NH(C1–C4 hydrocarbyl), —O—CO—N(R24)(R25), —N(R24)(R25), —S(C1–C4 hydrocarbyl), —S(C3–C5 cyclohydrocarbyl —N(C1–C4 hydrocarbyl)CO(C1–C4 hydrocarbyl), —NHCO(C1–C4 hydrocarbyl), —COO(C1–C4 hydrocarbyl), —CONH(C1–C4 hydrocarbyl), —CON(C1–C4 hydrocarbyl)(C1–C2 hydrocarbyl), CN, NO2, —OSO2(C1–C4 hydrocarbyl), S+(C1–C6 hydrocarbyl)(C1–C2 hydrocarbyl)I—, —SO(C1–C4 hydrocarbyl) and —SO2(C1–C4 hydrocarbyl);
• and wherein the C1–C6 hydrocarbyl, C1–C6 hydrocarbylene, C5–C8 cyclohydrocarbyl, C5–C8 cyclohydrocarbylene, and C5–C8 heterocyclohydrocarbyl moieties of R1 may optionally independently contain from one to three double or triple bonds;
• and wherein the C1–C4 hydrocarbyl moieties and C1–C6 hydrocarbyl moieties of R8 can optionally independently be substituted with hydroxy, amino, C1–C4 alkyl, aryl, —CH2-aryl1 C3–C5 cycloalkyl, or —O—(C1–C4 alkyl), and can optionally independently be substituted with from one to six fluoro, and can optionally contain one or two double or triple bonds;
• and wherein each heterocyclohydrocarbyl group of R1 contains from one to three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR12;
• R2 is hydrogen, C1–C12 hydrocarbyl, C3–C8 cyclohydrocarbyl, C4–C8 heterocyclohydrocarbyl, —(C1–C6 hydrocarbylene)(C3–C8 cyclohydrocarbyl), —(C3–C8 cyclohydrocarbylene)(C3–C8 cyclohydrocarbyl), —(C1–C6 hydrocarbylene)(C4–C8 heterocyclohydrocarbyl), —(C3–C6 cyclohydrocarbylene)(C4–C8 heterocyclohydrocarbyl), aryl, —(C1–C6 hydrocarbylene)aryl, or —(C3–C8 cyclohydrocarbylene)(aryl);
• wherein each of the foregoing R2 groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, and C1–C6 alkyl, wherein one of said one to three substituents can further be selected from bromo, iodo, C1–C6 alkoxy, —OH, —O—CO—(C1–C6 alkyl), —O—CO—N(C1–C4 alkyl)(C1–C2 alkyl), —S(C1–C6 alkyl), —S(O)(C1–C6 alkyl), —S(O)2(C1–C6 alkyl), S+(C1–C6 alkyl)(C1–C2 alkyl) I—, CN, and NO2;
• and wherein the C1–C12 hydrocarbyl, —(C1–C6 hydrocarbylene), and cyclohydrocarbyl groups of 5–8 carbon atoms, cyclohydrocarbylene groups of 5 to 8 carbon atoms and heterocyclohydrocarbyl groups of 5 to 8 atoms of R2 may optionally independently contain from one to three double or triple bonds;
• and wherein each heterocyclohydrocarbyl group of R2 contains from one to three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR12;
• or when R1 and R2 are as in —NHCHR1R2, —OCHR1R2, —SCHR1R2, —CHR1R2 or —NR1R2, R1 and R2 of B may form a 5- to 8-membered ring which may be saturated or contain one or two double bonds and in which one or two of the ring carbons may optionally be replaced by an oxygen, S(O)m, nitrogen or NR12;
• and which carbocyclic ring can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, C1–C4 alkyl, fluoro, chloro, bromo, iodo, CF3, —O—(C1–C4 alkyl), —O—CO—(C1–C4 alkyl), —O—CO—NH(C1–C4 alkyl), —O—CO—N(C1–C4 alkyl)(C1–C2 alkyl), —NH(C1–C4 alkyl), —N(C1–C2 alkyl)(C1–C4 alkyl), —S(C1–C4 alkyl), —N(C1–C4 alkyl)CO(C1–C4 alkyl), —NHCO(C1–C4 alkyl), —COO(C1–C4 alkyl), —CONH(C1–C4 alkyl), —CON(C1–C4alkyl)(C1–C2 alkyl), CN, NO2, —OSO2(C1–C4 alkyl), —SO(C1–C4 alkyl), and —SO(C1–C4 alkyl), wherein one of said one to three substituents can further be selected from phenyl;
• R3 is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano, methoxy, OCF3, NH2, NH(C1–C2 alkyl), N(CH3)2, —NHCOCF3, —NHCH2CF3, S(O)m(C1–C4 alkyl), CONH2, —CONHCH3, CON(CH3)2, —CF3, or CH2OCH3;
• R4 is hydrogen, C1–C4 hydrocarbyl, C3–C5 cycloalkyl, —(C1–C4 hydrocarbylene)(C3–C5 cycloalkyl), —(C3–C5 cycloalkylene)(C3–C6 cycloalkyl), cyano, fluoro, chloro, bromo, iodo, —OR24 C1–C6 alkoxy, —O— cycloalkyl), —O—(C1–C4 hydrocarbylene)(C3–C5 cycloalkyl), —O—(C3–C5 cycloalkylene)(C3–C5 cycloalkyl), —CH2SC(S)O(C1–C4 alkyl), CH2OCF3, CF3, amino, nitro, —NR24R25, —(C1–C4 hydrocarbylene)-OR24, —(C1–C4 hydrocarbylene)Cl, —(C1–C4 hydrocarbylene)NR24R25, —NHCOR24, —NHCONR24R25, —CH═NOR24, —NHNR24R25, —S(O)mR24, —C(O)R24, —OC(O)R24, —C(O)CN, —C(O)NR24R25, —C(O)NHNR24R25, and —COOR24, wherein the hydrocarbyl and hydrocarbylene groups of R4 may optionally independently contain one or two double or triple bonds and may optionally independently be substituted with one or two substituents R10 independently selected from hydroxy, amino, —NHCOCH3, —NHCOCH2Cl, —NH(C1–C2 alkyl), —N(C1–C2 alkyl)(C1–C2alkyl), —COO(C1–C4 alkyl), —COOH, —CO(C1–C4 alkyl), C1–C6 alkoxy, C1–C3 thioalkyl, cyano and nitro, and with one to four substituents independently selected from fluoro and chloro;
• R5 is aryl or heteroaryl and is substituted with from one to four substituents R27 independently selected from halo, C1–C10 hydrocarbyl, —(C1–C4 hydrocarbylene)(C3–C8 cycloalkyl), —(C1–C4 hydrocarbylene)(C4–C8 heterocycloalkyl), —(C3–C8 cycloalkyl), —(C4–C8 heterocycloalkyl), —(C3–C8 cycloalkylene)(C3–C8 cycloalkyl), —(C3–C8 cycloalkylene)(C4–C8 heterocycloalkyl), C1–C4 haloalkyl, C1–C4 haloalkoxy, nitro, cyano, —NR24R25, —NR24COR25, —NR24CO2R26, —COR24, —OR25, —CONR24R25, —CON(OR22)R23, —CO2R26, —C═N(OR22)R23, and —S(O)mR23;
• wherein said C1–C10 alkyl, C3–C8 cycloalkyl, (C1–C4 hydrocarbylene), (C3–C8 cycloalkyl), (C3–C8 cycloalkylene), and (C4–C8 heterocycloalkyl) groups can be optionally substituted with from one to three substituents independently selected form C1–C4 alkyl, C3–C8 cycloalkyl, (C1–C4 hydrocarbylene)(C3–C8 cycloalkyl), —(C3–C8 cycloalkylene)(C3–C8 cycloalkyl), C1–C4 haloalkyl, hydroxy, C1–C6 alkoxy, nitro, halo, cyano, —NR24R25, —NR24COR25, NR24CO2R26, —COR24, —OR25, —CONR24R25, CO2R26, —CO(NOR22)R25, and —S(O)mR23;
• and wherein two adjacent substituents of the R5 group can optionally form a 5–7 membered ring, saturated or unsaturated, fused to R5, which ring optionally can contain one, two, or three heterologous members independently selected from O, S(O)m, and N, but not any —S—S—, —O—O—, —S—O—, or —N—S— bonds, and which ring is optionally substituted with C1–C4 alkyl, C3–C8 cycloalkyl, —(C1–C4 alkylene)(C3–C8 cycloalkyl), —(C3–C8 cyloalkylene)(C3–C8 cycloalkyl), C1–C4 haloalkyl, nitro, halo, cyano, —NR24R25, NR24COR25, NR24CO2R26, —COR24, —OR25, —CONR24R25, CO2R26, —CO(NOR26)R25, or —S(O)mR23;
• wherein one of said one to four optional substituents R27, can further be selected from —SO2NH(C1–C4 alkyl), —SO2NH(C1–C4 alkylene)(C3–C8 cycloalkyl), SO2NH(C3–C8 cycloalkyl), —SO2NH(C3–C8 cycloalkylene)(C3–C8 cycloalkyl), —SO2N(C1–C4 alkyl)(C1–C2 alkyl), —SO2NH2, —NHSO2(C1–C4 alkyl), —NHSO2(C3–C8 cycloalkyl), —NHSO2(C1–C4 alkylene)(C3–C8 cycloalkyl), and —NHSO2(C3–C8 cycloalkylene)(C3–C8 cycloalkyl);
• and wherein the hydrocarbyl, and hydrocarbylene groups of R5 may independently optionally contain one double or triple bond;
• R6 is hydrogen, C1–C6 alkyl, C3–C8 cycloalkyl, —(C1–C6 alkylene)(C3–C8 cycloalkyl), or —(C3–C8 cycloalkylene)(C3–C8 cycloalkyl), wherein said alkyl and cycloalkyl may optionally be substituted with one hydroxy, methoxy, ethoxy or fluoro group;
• or R6 and R4 can together form an oxo (═O) group, or can be connected to form a 3–8 membered carbocyclic ring, optionally containing one to three double bonds, and optionally containing one, two, or three heterologous ring members selected from O, SOm, N, and NR12, but not containing any —O—O—, —S—O—, —S—S—, or —N—S— bonds, and further optionally substituted with C1–C4 hydrocarbyl or C3–C6 cycloalkyl, wherein said C I—C4 hydrocarbyl substituent may optionally contain one double or triple bond;
• R7 is hydrogen, methyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, —O(C1–C2 alkyl), —O(cyclopropyl), —COO(C1–C2 alkyl), —COO(C3–C8 cycloalkyl), —OCF3, CF3, —CH2OH, or CH2OCH3;
• R11 is hydrogen, hydroxy, fluoro, ethoxy, or methoxy;
• R12 is hydrogen or C1–C4 alkyl;
• R16 and R17 are each, independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy, except that R16 and R17 are not both methoxy or ethoxy;
• or R16 and R17 together form an oxo (═O) group;
• or R16 and R17 are connected to form a 3–8 membered carbocyclic ring, optionally containing one to three double bonds, and optionally containing from one to three heterologous ring members selected from O, SOm, N, and NR12, but not containing any —O—O—, —S—O—, —S—S—, or —N—S— bonds, and further optionally substituted with C1–C4 hydrocarbyl or C3–C6 cycloalkyl, wherein said C1–C4 hydrocarbyl substituent may optionally contain one double or triple bond;
• R22 is independently at each occurrence selected from hydrogen, C1–C4 alkyl, C1–C4 haloalkyl, C3–C6 alkenyl, C3–C6 alkynyl, C3–C8 cycloalkyl, (C3–C8 cycloalkylene)(C3–C8 cycloalkyl), and (C1–C4 alkylene)(C3–C8 cycloalkyl);
• R22 is independently at each occurrence selected from hydrogen, C1–C14 alkyl, C1–C14 haloalkyl, C3–C6 alkenyl, C3–C6 alkynyl, C3–C8 cycloalkyl, (C3–C8 cycloalkylene)(C3–C8 cycloalkyl), and (C1–C4)alkylene)(C3–C8 cycloalkyl);
• R23 is independently at each occurrence selected from C1–C4 alkyl, C1–C4 haloalkyl, C2–C8 alkoxyalkyl, C3–C8 cycloalkyl, —(C1–C4 alkylene)(C3–C8 cycloalkyl), —(C3–C8 cycloalkylene)(C3–C8 cycloalkyl), aryl, —(C1–C4 alkylene)aryl, piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, and thiomorpholine;
• R24 and R25 are independently at each occurrence selected from hydrogen, —C1–C4 alkyl, C1–C4 haloalkyl, —(C1–C4 alkylene)OH, —(C1–C4 alkylene)-O—(C1–C4 alkyl), —(C1–C4 alkylene)-O—(C3–C5 cycloalkyl), C3–C8 cycloalkyl, —(C1–C4 alkylene)(C3–C8 cycloalkyl), —(C3–C8 cycloalkylene)(C3–C8 cycloalkyl), —C4–C8 heterocyclohydrocarbyl, —(C1–C4 alkylene)(C4–C8 heterocyclohydrocarbyll), —(C3–C8 cycloalkylene)(C4–C8 heterocyclohydrocarbyl), aryl, and —(C1–C4 alkylene)(aryl), wherein the —C4–C8 heterocyclohydrocarbyl groups can each independently optionally be substituted with aryl, CH2-aryl, or C1–C4 hydrocarbyl, and can optionally contain one or two double or triple bonds;
• or, when R24 and R25 are as NR24R25, —C(O)NR24R25, —(C1–C4 alkylene)NR24R25, or —NHCONR24R25, then NR24R25 may further optionally form a 4 to 8 membered heterocyclic ring optionally containing one or two further hetero members independently selected from S(O)m, oxygen, nitrogen, and NR12, and optionally containing from one to three double bonds;
• R26 is independently at each occurrence selected from C1–C4 alkyl, C1–C4 haloalkyl, C3–C8 cycloalkyl, —(C1–C4 alkylene)(C3–C8 cycloalkyl), —(C3–C8 cycloalkylene)(C3–C8 cycloalkyl), aryl, and —(C1–C4 alkylene)(aryl);
• and
• wherein each m is independently zero, one, or two,
• with the proviso that heterocyclohydrocarbylene groups of the compound of formula II, do not comprise any —S—S—, —S—O—, —N—S—, or —O—O— bonds, and do not comprise more than two oxygen or S(O)m heterologous members.